Temporomandibular disorders (TMD) are associated with chronic and debilitating pain. These far too common disorders, affecting up 15% of American adults, are often resistant to traditional therapies effective for pain treatment in other areas of the body, possibly reflecting unique properties of primary afferent neurons innervating the temporomandibular joint (TMJ). Furthermore, there is an increased prevalence and severity of TMD pain in women versus men. Epidemiological, clinical, and animal experimental evidence suggests that estrogen may contribute to the pathophysiology of TMD pain. Therefore, we propose to test the hypothesis that estrogen increases the excitability of trigeminal primary afferent neurons innervating the TMJ Pain associated with TMD may also reflect TMJ inflammation. In the presence of inflammation, primary afferent neurons become sensitized, displaying spontaneous activity and/or a leftward shift in the stimulus- response function. Therefore, we also propose to test the hypothesis that estrogen exacerbates the inflammation-induced sensitization of primary afferent neurons innervating the TMJ. To test these hypotheses, we will perform experiments described under the following Specific Aims.